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The Capital Region of Denmark - a part of Copenhagen University Hospital
E-pub ahead of print

Systemic inflammation is linked to liver fibrogenesis in patients with advanced chronic liver disease

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  • Benedikt Simbrunner
  • Ida Falk Villesen
  • Philipp Königshofer
  • Bernhard Scheiner
  • David Bauer
  • Rafael Paternostro
  • Philipp Schwabl
  • Gerald Timelthaler
  • Dariga Ramazanova
  • Katharina Wöran
  • Judith Stift
  • Ernst Eigenbauer
  • Albert Friedrich Stättermayer
  • Rodrig Marculescu
  • Matthias Pinter
  • Søren Møller
  • Michael Trauner
  • Morten Karsdal
  • Diana Julie Leeming
  • Thomas Reiberger
  • Mattias Mandorfer
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BACKGROUND & AIMS: Experimental evidence indicates that systemic inflammation (SI) promotes liver fibrogenesis. This study investigated the potential link between SI and fibrogenesis in patients with advanced chronic liver disease (ACLD).

METHODS: Serum biomarkers of SI (CRP, IL-6, procalcitonin [PCT]) and extracellular matrix (ECM) turnover (i.e., fibrogenesis/fibrolysis) were analysed in 215 prospectively recruited patients with ACLD (hepatic venous pressure gradient [HVPG] ≥6mmHg) undergoing hepatic vein catheterization. Patients with non-elective hospitalization or bacterial infection were excluded. Histological alpha-smooth muscle actin (α-SMA) area was quantified on full biopsy-scans by automated morphometric quantification in a subset of 34 patients who underwent concomitant transjugular liver biopsy.

RESULTS: Histological α-SMA proportionate area correlated with enhanced liver fibrosis (ELF) score (Spearman's ρ=0.660,p<0.001), markers of collagen formation (PRO-C3, ρ=0.717,p<0.001; PRO-C6, ρ=0.526,p=0.002), and tissue inhibitor of metalloproteinases-1 (TIMP1; ρ=0.547,p<0.001), indicating that these blood biomarkers are capable of reflecting the dynamic process of ECM turnover. CRP, IL-6, and PCT levels correlated with ELF, biomarkers of collagen synthesis/degradation, and TIMP1, both in compensated and decompensated patients. Multivariate linear regression models (adjusted for HVPG) confirmed that CRP, IL-6, and PCT were independently linked to markers of liver fibrogenesis and ECM turnover.

CONCLUSION: Systemic inflammation is linked to both liver fibrogenesis and ECM turnover in ACLD and this association is not confounded by the severity of liver disease, as evaluated by HVPG. Our study confirms experimental data on the detrimental impact of SI on ECM deposition and fibrosis progression in a thoroughly characterized cohort of patients with ACLD.

Original languageEnglish
Article number15365
JournalLiver international : official journal of the International Association for the Study of the Liver
Pages (from-to)1-41
Number of pages41
ISSN1478-3223
DOIs
Publication statusE-pub ahead of print - 13 Jul 2022

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